The present invention relates to novel indolylpiperidine compounds and pharmacologically acceptable salts thereof which have antihistaminic activity and antiallergic activity and are useful as medicaments for the treatment of bronchial asthma, allergic rhinitis, conjunctivitis, dermatosis, urticaria and the like.
The present invention also relates to a method for preparing the indolylpiperidine compounds, pharmaceutical compositions useful for the treatment of allergic diseases and bronchial asthma which comprises an effective amount of the indolylpiperidine compound.
Several antihistaminics and antiallergic agents are known which have indolylpiperidine structures. Examples of indolylpiperidine compounds represented by the following formula: 
(where Rxe2x95x90H, OH, ORxe2x80x2 and n=2-6) are described in Shigenaga, S. et al., Arch. Pharm. Med. Chem.(1996) 329:3-10.
Furthermore, as compounds useful for the treatment of allergic diseases, EP 224919 discloses for example the compounds represented by the following formula: 
(where R1=opt.subst.amino; R2xe2x95x90H, lower alkyl or aryl; R3xe2x95x90H, NO2, opt.subst.amino, OH or lower alkoxy; A=lower alkylene; Q=H or halogen).
Most of these compounds are characterized as antiallergic agents useful for treating allergic asthma, rhinitis, conjunctivitis and urticaria.
Current antihistamines cannot be considered to be fully satisfactory from a safety point of view and problems remain with respect to adverse reactions such as sleepiness, sedation, hydrodipsia, mydriasis, palpitation and arrhythmia mediated through their undesirable penetration of the central nervous system, antiacetylcholinergic activity, activity against cardiovascular system or the like. Consequently, the clinical need exists for antihistamines and antiallergic agents which are largely devoid of sedative and cardiovascular side-effects.
The present invention provides novel indolylpiperidine compounds having improved antihistamine and antiallergic activity.
The present invention also provides novel indolylpiperidine compounds which due to their lack of lipophilic properties are almost totally unable to penetrate into the brain and hence lack sedative secondary effects. It can also be understood that the compounds of the present invention have reduced cardiovascular side effects.
A further objective of the present invention is to provide a method for preparing said compounds.
Yet another objective is to provide a pharmaceutical composition comprising an effective amount of said compounds.
In accordance with the present invention, novel indolylpiperidine compounds represented by the formula I are provided: 
wherein:
A1 represents an alkylene, alkyleneoxy, alkylenethio, alkanoyl or hydroxyalkylene group;
A2 represents a single bond, an alkylene or alkenylene group;
W represents a single bond or a phenylene or furanylene group which is unsubstituted or substituted by one or more halogen atoms, alkoxy groups and/or alkyl groups;
R1 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl alkoxy-alkoxyalkyl, phenylalkyl group wherein the phenyl ring is unsubstituted or substituted by one or more halogen atoms or alkyl, alkoxy or arylalkoxy (preferably phenylalkoxy) groups, or a cycloalkylalkyl group wherein the cycloalkyl group is unsubstituted or substituted by one or more halogen atoms, alkyl groups or alkoxy groups;
R2 represents a hydrogen or halogen atom or an alkyl or alkoxy group; and
R3 represents a carboxyl group or a tetrazolyl group;
and pharmaceutically acceptable salts thereof.
In the above formula (I), the alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkyleneoxy, alkylenethio, alkanoyl, hydroxyalkylene and alkoxy groups mentioned in relation to the groups A1, A2, R1 and R2 in the compounds of the invention, may be branched or straight and are preferably xe2x80x9clowerxe2x80x9d alkyl, alkenyl or alkynyl moieties, that is containing up to 7 and particularly up to 5 carbons atoms.
The cycloalkyl group mentioned in relation to R1 may be mono or polycyclic, preferably mono or bicyclic and most preferably monocyclic. The cycloalkyl group preferably contains from 3 to 14, more preferably from 3 to 10 and most preferably from 3 to 7 carbon atoms.
In accordance with another embodiment of the present invention, the present invention provides a method for preparing the compound represented by formula I.
In accordance with yet another embodiment of the present invention, the present invention provides a pharmaceutical composition comprising an effective amount of the compound represented by formula I together with a pharmaceutically acceptable carrier or coating.
In accordance with a further embodiment, the present invention provides a method for treating an allergic disease or bronchial asthma comprising the step of administering an effective amount of the compound represented by formula I. Further features and advantages of the present invention will become apparent from the Description of the Preferred Embodiment which follows, when read in the light of the attached Examples and Reference Examples.
In preferred compounds of the invention A1 represents an alkylene, alkyleneoxy, hydroxyalkylene or alkylenethio group.
In preferred compounds of the invention A2 represents a single bond or a C1-4 alkylene or C2-5 alkenylene group.
In preferred compounds of the invention W represents a furanylene group or a phenylene group which is unsubstitued or substituted by one or two fluorine, chlorine or bromine atoms, methyl groups or methoxy groups. It will be understood that, in compounds of the invention wherein W is other than a single bond, the phenylene or furanylene group may be substituted by A1 and A2 or, in the case that A2 is a single bond, R3 at any combination of substitutable ring positions relative to each other, for example 1,2; 1,3; or 1,4. In compounds of the invention wherein the phenylene or furanylene ring is further substituted for example by halogen atoms, alkyl groups and/or alkoxy groups, then the further substituents may be attached at any of the remaining available positions on the ring.
In preferred compounds of the invention R1 represents a C1-7 alkyl, alkenyl or alkynyl group, a C2-5 alkoxyalkyl group, a C3-7 alkenoxy-alkyl group, a C3-7 alkynoxy-alkyl group, a C3-7 alkoxy-alkoxyalkyl group, a benzyl or phenylethyl group which is unsubstituted or substituted by one or more halogen atoms, C1-4 alkyl, methoxy or benzyloxy groups or a cycloalkylalkyl group wherein the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or decalinyl which is unsubstituted or substituted by one or more halogen atoms, C1-4 alkyl or methoxy groups and the alkyl part of the cycloalkylalkyl group is methylene, ethylene, propylene or butylene.
In preferred compounds of the invention R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group. It will be understood that the substituent R2 may be attached at the 4, 5, 6 or 7 position of the indolyl nucleus.
More preferred compounds of formula I are those in which A1 represents a methylene, ethylene, propylene, butylene, pentylene, hexylene, ethyleneoxy, propyleneoxy, hydroxybutylene, ethylsulfanyl or butylsulfanyl group; A2 represents a single bond or a methylene, ethylene, propylene, methylethylene, butylene or ethenylene group; W represents an unsubstituted furanylene, unsubstituted phenylene, fluorophenylene, dibromophenylene, methylphenylene or methoxyphenylene group; R1 represents a hydrogen atom or a propyl, butyl, isobutyl pentyl, hexyl, heptyl, 2-methylpropyl, 3-methylbutyl, allyl, propenyl, propynyl, methoxyethyl, methoxypropyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, prop-2-ynyloxyethyl, prop-2-enyloxyethyl, methoxyethoxyethyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-(tert-butyl)-benzyl, 4-benzyloxybenzyl, 4-methoxyphenylethyl, cyclopropylmethyl, cyclopropylethyl or cyclopropylpropyl group; R2 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxy group; and R3 is a carboxyl or a tetrazolyl group.
The pharmacologically acceptable salts of the compounds of the present invention represented by formula I may be acid addition salts or alkali addition salts. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.
Examples of the alkali addition salts include inorganic salts such as, for example sodium, potassium, calcium and ammonium salts and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic aminoacids salts.
The compounds of the present invention represented by the above-described formula (I) may include enantiomers depending on their asymmetry or diastereoisomers. The single isomers and mixtures of the isomers fall within the scope of the present invention.
Although the preferred indolylpiperidine compounds of the present invention include the following compounds, the present invention will not be limited to these examples,
1. 2-(2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
2. 2-{2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
3. 4-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-butyric acid
4. 3-(3-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzoic acid
5. 4-{3-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy)-benzoic acid
6. 2-[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-benzoic acid
7. 3-[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-benzoic acid
8. 3-(2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
9. 3-{2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
10. 3-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl-ethoxy)-benzoic acid
11. 4-[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-benzoic acid
12. 4-{2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
13. 2-[3-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-propoxy]-benzoic acid
14. 2-(3-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzoic acid
15. 2-{3-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy}-benzoic acid
16. 2-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzoic acid
17. 3-[3-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-propoxy]-benzoic acid
18. 3-{3-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy}-benzoic acid
19. 3-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzoic acid
20. 4-[3-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-propoxy]-benzoic acid
21. 4-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-benzoic acid
22. 3-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-propionic acid
23. 3-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-propionic acid
24. 4-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-butyric acid
25. 4-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-butyric acid
26. 4-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-butyric acid
27. 3-{4-[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethyl]-phenyl}-propionic acid
28. 3-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-propionic acid
29. 3-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethyl)-phenyl]-propionic acid
30. 3-{4-[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethyl]-phenyl}-acrylic acid
31. 3-(4-{2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethyl}-phenyl)-acrylic acid
32. 3-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethyl)-phenyl]-acrylic acid
33. 2-{4-[1-hydroxy-4-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-butyl]-phenyl}-2-methyl-propionic acid
34. 2-(4-{1-hydroxy-4-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-butyl}-phenyl)-2-methyl-propionic acid
35. 2-[4-(4-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-1-hydroxy-butyl)-phenyl]-2-methyl-propionic acid
36. [2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-acetic acid
37. (2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid
38. {2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-acetic acid
39. (2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid
40. 5-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl-methyl)-furan-2-carboxylic acid
41. 5-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl-methyl]-furan-2-carboxylic acid
42. 5-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl-methyl}-furan-2-carboxylic acid
43. 5-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-furan-2-carboxylic acid.
44. 2-[4-(4-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-1-hydroxy-butyl)-phenyl]-2-methyl-propionic acid
45. 2-{2-[4-(1-heptyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
46. 2-(2-{4-[1-(4-tert-butyl-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
47. 2-(2-{4-[1-(4-methoxy-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
48. 2-(2-{4-[1-(4-benzyloxy-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
49. 2-{2-[4-(1-iso-butyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
50. 2-[2-(4-{1-[2-(4-methoxy-phenyl)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-benzoic acid
51. 2-(4-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid
52. 2-(4-{4-[4-(1H-indol-3-yl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl-propionic acid
53. 2-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
54. 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
55. 4-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
56. (3-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-phenyl)-acetic acid
57. (3-{3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propoxy}-phenyl)-acetic acid
58. (4-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-phenyl)-acetic acid
59. (4-{3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propoxy}-phenyl)-acetic acid
60. 3-(1-{3-[3-(1H-tetrazol-5-yl)-phenoxy]-propyl}-piperidin-4-yl)-1H-indole
61. 2-methyl-2-[4-(2-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-ethyl)-phenyl]-propionic acid
62. 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid
63. 2-methyl-2-[4-(4-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-butyryl)-phenyl]-propionic acid
64. 2-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-benzoic acid
65. 2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-benzoic acid
66. 3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-benzoic acid
67. 4-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-ylmethyl}-benzoic acid
68. [3-(2-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-phenyl]-acetic acid
69. [3-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-phenyl]-acetic acid
70. [3-(3-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-phenyl]-acetic acid
71. [3-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-phenyl]-acetic acid
72. [4-(2-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-phenyl]-acetic acid
73. [4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-phenyl]-acetic acid
74. [4-(3-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-phenyl]-acetic acid
75. [4-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-phenyl]-acetic acid
76. 2-{2-[4-(1-prop-2-ynyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
77. 2-methyl-2-[4-(4-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-butyryl)-phenyl]-propionic acid
78. 1-(2-ethoxy-ethyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)-phenoxy]-propyl}-piperidin-4-yl)-1H-indole
79. 1-(3-methyl-butyl)-3-(1-{3-[2-(2H-tetrazol-5-yl)-phenoxy]-propyl}-piperidin-4-yl)-1H-indole
80. 1-(3-methyl-butyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-propyl}-piperidin-4-yl)-1H-indole
81. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-methoxy-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
82. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
83. 2-(2-{4-[1-(2-ethoxy-ethyl)-6-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
84. 2-(2-{4-[5-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
85. 2-(2-{4-[7-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
86. 2-(2-{4-[5-chloro-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
87. 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-6-fluoro-benzoic acid
88. 3,5-dibromo-2-(2-{4-[1-(2-ethoxy-ethyl)-5-methoxy-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
89. 3,5-dibromo-2-(2-{4-[1-(2-ethoxy-ethyl)-5-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
90. 3,5-dibromo-2-(2-{4-[1-(2-ethoxy-ethyl)-6-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
91. 3,5-dibromo-2-(2-{4-[5-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
92. 3,5-dibromo-2-(2-{4-[7-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
93. 3,5-dibromo-2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
94. 2-(2-{4-[1-(2-ethoxy-ethyl)-6-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
95. 2-(2-(4-[5-chloro-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
96. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-methoxy-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
97. 2-(2-{4-[1-(2-ethoxy-ethyl)-6-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
98. 2-(2-{4-[5-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
99. 2-(2-{4-[7-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
100. 2-(2-{4-[5-chloro-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
101. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-methoxy-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
102. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
103. 2-(2-{4-[1-(2-ethoxy-ethyl)-6-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
104. 2-(2-{4-[5-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
105. 2-(2-{4-[5-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
106. 2-(2-{4-[5-chloro-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
107. 2-{2-[4-(1-propyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
108. 2-(2-{4-[1-(2-iso-propoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
109. 2-(2-{4-[1-(3-methoxy-propyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
110. 2-(2-{4-[1-(2-ethoxy-ethyl)-4-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
111. 2-(2-{4-[1-(2-ethoxy-ethyl)-4-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
112. 2-(2-{4-[1-(2-ethoxy-ethyl)-4-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
113. 2-(2-{4-[4-fluoro-1-(2-methoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
114. 2-(2-{4-[4-fluoro-1-(2-methoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
115. 2-(2-{4-[4-fluoro-1-(2-methoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
116. 5-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-pentanoic acid
117. 6-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-hexanoic acid
118. 7-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-heptanoic acid
119. 3-(3-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-propoxy)-propionic acid
120. 2-(2-{4-[1-(2-ethoxy-ethyl)-7-methyl-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
121. 2-(2-{4-[6-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
122. 2-(2-{4-[6-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
123. (2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethylsulfanyl)-acetic acid
124. (4-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-butylsulfanyl)-acetic acid
125. (3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy}-phenyl)-acetic acid
126. (4-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-phenyl)-acetic acid
127. (3-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-phenyl)-acetic acid
128. 3-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
129. 5-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-furan-2-carboxylic acid
130. 3-[4-(6-fluoro-1-pentyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
131. 2-(4-{4-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-butyryl}-phenyl)-2-methyl-propionic acid
132. 3-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy}-benzoic acid
133. 2-{2-[4-(1-cyclohexylmethyl-1H-indol-3-yl)-piperidin-1-yl]ethoxy}-benzoic acid
134. 2-(2-{4-[1-(2-allyloxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
135. 2-(2-{4-[1-(2-prop-2-ynyloxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
136. 2-(2-{4-[1-(2-propoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
137. 4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
138. 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
139. 2-(2-{4-[1-(3-methyl-butyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
140. 2-(2-{4-[1-(2-methoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
141. 2-{2-[4-(1-allyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
142. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-methoxy-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
143. 2-(2-{4-[7-bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
144. 2-(2-{4-[7- bromo-1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
145. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
146. 2-(2-{4-[1-(2-ethoxy-ethyl)-5-fluoro-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid
147. 2-(2-{4-[1-(2-ethoxy-ethyl)-7-methyl-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid
148. 2-{2-[4-(1-butyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
149. 2-{2-[4-(1-hexyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
150. 2-{2-[4-(1-cyclopropylmethyl-6-fluoro-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
151. 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
153. 3-{4-[1-(2-ethoxyethyl)-1H-indol-3-yl]-piperidin-1-yl}-propionic acid
154. 2-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-5-methyl-benzoic acid
155. 2-[4-(4-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-butyryl)-phenyl]-2-methyl-propionic acid
156. 1-(2-ethoxy-ethyl)-3-(1-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-propyl}-piperidin-4-yl)-1H-indole
157. 2-{2-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid
158. 3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid
159. (4-{3-[4-(1-cyclopropylmethyl-1H-indol-3-yl)-piperidin-1-yl]-propoxy}-phenyl)-acetic acid
The novel indolylpiperidine compounds of the present invention represented by formula I can be prepared according to Scheme 1 from the corresponding piperidine derivative of formula II: 
wherein R2 is as defined above, with a reactive intermediate of general formula III:
Xxe2x80x94A1xe2x80x94Wxe2x80x94A2xe2x80x94R4xe2x80x83xe2x80x83(III) 
wherein A1, A2 and W are as defined above, R4 is a nitrile group or a xe2x80x94COOR5 group where R5 is a C1-C4 alkyl group and X is a leaving group such as a chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group.
The reaction is preferably carried out in an inert organic solvent such as toluene, dioxane or methyl isobutyl ketone, at a temperature between 80xc2x0 C. and 140xc2x0 C. and in the presence of an inorganic base such as an alkali metal carbonate or bicarbonate. In the reaction, the corresponding alkylation product of general formula IV is formed: 
Compound IV is alkylated on the indole nitrogen with a reactive intermediate of general formula V:
R1xe2x80x94Xxe2x80x83xe2x80x83(V) 
wherein X is a leaving group such as chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group and R1 as defined above.
The reaction is preferably carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or ethyl ether, at a temperature between 0xc2x0 C. and 80xc2x0 C. in the presence of an inorganic base such as sodium hydride or sodium amide. In the reaction, the corresponding alkylation product 
of general formula VI is formed (see Scheme 1).
Alternatively, the alkylation sequence yielding intermediate VI can be reversed starting from the compound of general formula VII where R2 is as defined above. 
Compound VII is alkylated on the indole nitrogen with a reactive intermediate of general formula V:
R1xe2x80x94Xxe2x80x83xe2x80x83(V) 
wherein X is a leaving group such as chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group and R1 as defined above. This reaction leads to compound VIII (see Scheme 1), wherein R1 and R2 are defined 
as above.
The reaction is preferably carried out in an inert organic solvent such as dimethylformamide, tetrahydrofurane or ethyl ether, at a temperature between 0xc2x0 C. and 80xc2x0 C. in the presence of an inorganic base such as sodium hydride or sodium amide.
Subsequent deprotection of compound VIII (see Scheme 1), first by boiling it in the presence of an excess of sodium or potassium hydroxide in a alcoholic solvent such as ethanol, isopropanol or n-butanol in a temperature between 80xc2x0 C. and 180xc2x0 C. and then neutralised with an inorganic acid such as hydrochloric or sulfuric acid, leads to the general structure IX (see Scheme 1), wherein R1 and R2 are defined as above. 
Further alkylation of compound IX with a reactive inter mediate of general formula (III)
Xxe2x80x94A1xe2x80x94Wxe2x80x94A2xe2x80x94R4xe2x80x83xe2x80x83(III) 
wherein A1, A2 and W are as defined above, R4 is a nitrile group or a xe2x80x94COOR5 group where R5 is a C1-C4 alkyl group and X is a leaving group such as chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group. The reaction is preferably carried out in an inert organic solvent such as toluene, dioxane or methyl isobutyl ketone, at a temperature between 80xc2x0 C. and 140xc2x0 C. in the presence of an inorganic base such as an alkali metal carbonate or bicarbonate. In the reaction, the corresponding alkylation product of general formula VI is formed (see Scheme 1).
Compounds of general formula VI where R4 represents an alkyl ester are treated with sodium or potassium hydroxide and further treatment with an inorganic acid such as hydrochloric or sulfuric acid provides the corresponding indole derivative of formula I where R3 is a carboxylic acid. The reaction is preferably carried out in a solvent such as methanol, ethanol, tetrahydrofuran or an aqueous mixture of one of the above mentioned solvents at its boiling point.
When R4 is a nitrile group, the reaction to yield the tetrazole is preferably carried out in presence of sodium azide in an organic solvent such as N,N-dimethyl formamide or N-methyl pyrrolidone, at a temperature between 60xc2x0 C. and 180xc2x0 C. for 10 to 20 hours, in presence of an inorganic acid such as hydrochloric acid. The corresponding compounds of general formula X are formed: 
wherein A1, A2, R1, R2 and W are as defined above.
On the other hand, compounds of general formula IV are alkylated in the indol nitrogen with 2-(2-bromo-ethoxy)-tetrahydro-pyran to give compounds of general structure XI, wherein A1, A2, R2 and R4 are as defined above (see scheme 2). This reaction is preferably carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or ethyl ether at a temperature between 0xc2x0 C. and 80xc2x0 C. in the presence of a inorganic base such as sodium hydride or sodium amide. Subsequent deprotection of compound XI boiling it in the presence of hydrogen chloride in a alcoholic solvent such as ethanol, methanol or isopropanol leads to a compound of general structure XII wherein A1, A2, R2, R4 and W are as defined above. Further alkylation of the compound XII with an intermediate of general formula R6xe2x80x94X (XIII) where R6 is a C1-C3 alkyl, alkenyl or alkynyl group and X is a leaving group such a chloride or a bromide atom or a methane sulfonate, p-toluenesulfonate or benzenesulfonate group, leads to a compound of general structure XIV, where A1, A2, R2, R4, R6 and W are as defined above. 
This reaction is preferably carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or ethyl ether at a temperature between 0xc2x0 C. and 80xc2x0 C. in the presence of a inorganic base such as sodium hydride or sodium amide. Compounds of general formula XIV where R4 represents an alkyl ester are treated with sodium or potasium hydroxide and further treatment with an inorganic acid provides the corresponding indole derivative of formule XV, wherein A1, A2, W, R2, and R6 are as defined above and R3 is a carboxylic acid. 
This reaction is preferably carried out in a solvent such as methanol, ethanol, tetrahydrofuran or an aqueous mixture of the above mentioned solvents at its boiling point. The products are purified by chromatography or by crystallization. High yields, between 70% and 90%, are normally obtained.
If necessary, an excess of the reagent is employed to ensure complete reaction, and a polymer, such as a methyl isocyanate polystyrene or/and 3-(3-mercapto-phenyl)-propan-amido-methyl polystyrene may be conveniently added to react with the excess reagent. Isolation of products from reactions where a polymer bond reagent has been used is greatly simplified, requiring only filtration under reduced pressure.
The product from these reactions may be purified by solid phase extraction, using a suitable sorbent, such as Varian SCX, or Varian C18.
The piperidine derivatives of formula (II) can be prepared from the 4-piperidone as disclosed in the literature (J. Med. Chem. 1992, 35, 4813-4822). The reactive intermediates of general formula (III) can be prepared as disclosed in the literature. 
Also included within the scope of the present invention are pharmaceutical compositions which comprise, as the active ingredient, at least one indolylpiperidine derivative of general formula (I), or a pharmacologically-acceptable salt thereof, in association with a pharmaceutically-acceptable carrier or diluent. Preferably the composition is made up in a form suitable for oral, or parenteral administration.
The pharmaceutically-acceptable carriers or diluents which are mixed with the active compound or compounds, or salts thereof, to form the composition of this invention are well-known xe2x80x9cper sexe2x80x9d and the actual excipients used depend xe2x80x9cinter aliaxe2x80x9d on the intended method of administration of the compositions.
Compositions of this invention are preferably adapted for oral administration. In this case, the composition for oral administration may take the form of tablets, capsules or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention; such preparations may be made by methods well known in the art.
The diluents which may be used in the preparations of the compositions include those liquid and solid diluents which the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 0.2 and 500 mg, preferably from 1 to 100 mg, of active ingredient or the equivalent amount of a pharmacologically-acceptable salt thereof. The compounds may be incorporated into pellets coated with an appropriate natural or synthetic polymers known in the art to produce sustained release characteristics or incorporated with polymers into tablets form to produce the same characteristics.
The liquid composition adapted for oral use may be in the form of solution or suspension. The solutions may be aqueous solution of an acid addition salt of the indolylpiperidine derivative in association with, for example, sucrose or sorbitol to form a syrup. The suspension may comprise an insoluble or micro encapsulated form of an active compound of the invention in association with water of other pharmaceutically-acceptable liquid medium together with a suspending agent or flavouring agent.
Composition for parenteral injection may be prepared from soluble salts of the indolylpiperidine derivative, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injectable fluid.
In human therapy, the doses of the compound of general formula (I) depend on the desired effect and duration of treatment; adult doses are generally between 0.2 mg and 500 mg per day and preferably between 1 mg and 100 mg per day. In general, the physician will decide the dosing regime taking into account the age and weight of the patient being treated.
Pharmacological Action
The following examples demonstrate the excellent pharmacological activities of the compounds of the present invention. The results of (1) Histamine-H1 receptor binding assay, (2) histamine-induced skin vascular permeability in rats with the monitoring of antiallergic activity, (3) H1 ex vivo binding studies in mice with the monitoring of degree of penetration into brain and (4) measurement of blood pressure and heart rate in conscious unrestrained hypertensive rats with the monitoring of cardiovascular effects, were obtained as described below.
(1) Histamine-H1 receptor binding assay
Binding to the histamine-H1 receptors was performed in guinea pig cerebellum membranes as described previously (Chang, Raymond S.L. et al., Journal of Neurochemistry (1979) 32:1653-1663). Briefly, the membrane suspensions (160 xcexcg/ml) were incubated at 30xc2x0 C. with 0.7 nM [3H]- mepyramine and different concentrations of the test compounds in a final volume of 250 xcexcl. Binding reactions were terminated by filtration after 30 min of incubation and the bound radioactivity was determined. The specific binding was measured in the presence of 10 xcexcM of promethazine. The affinity of each test compound to the receptor was determined by using at least six different concentrations run in duplicate. IC50 values were obtained by non-linear regression by use of SAS on a DEC AXP computer.
Our results show that the compounds of the present invention have affinities for the H1 receptors very similar to the reference compounds.
(2) Histamine-induced skin vascular permeability in rats
Male Wistar rats (180-210 g) were treated orally with the test compound or vehicle. One, 4, 8 and 24 hours later, the rats were lightly anaesthetized with ether. The cutaneous reaction was induced by two intradermal injections of 50 xcexcl of histamine (100 xcexcg/ml) onto the back, followed by a intravenous injection of 3 ml/kg of Evan""s Blue (5 mg/ml), both dissolved in saline. Sixty min later, the rats were killed by cervical dislocation and the back skin dissected free. The diameter (in millimeters) of the wheal was measured in two directions and the area was calculated. Results are given as the % of inhibition at a given dose compared with the vehicle treated group.
The compounds disclosed in examples 2, 41, 108, 138, 140, 141, 142, 148, 149, 150, 157 and 158 show an inhibition greater than 50% of the histamine-induced wheal at the dose of 3 mg/Kg 4 hours after administration (in the same experimental conditions, cetirizine and fexofenadine show an inhibition of 36% and 21%, respectively).
(3) H1 ex vivo binding studies in mice
The assay was performed essentially as described by Leysen, Josee E. et al., Drug Development Research (1991) 22:165-178, with the following modifications. Overnight starved male Swiss albino mice ((21 xc3x852 g) were treated orally with different doses of the test compounds (10 ml/kg, p.o.) and 90 minutes later were killed. The whole brain was dissected out and homogenized in 10 ml of ice-cold 0.05 M Na+/K+ phosphate buffer (pH 7.4). A 1 ml aliquot of the homogenate was incubated, in triplicate, with 0.1 ml [3H]-mepyramine (2 nM final concentration, 27 Ci/mmol, Amersham) during 40 minutes at 30xc2x0 C. The [3H]-mepyramine bound to the membranes was determined by immediate filtration of the homogenates under vacuum onto the glass fibre filters (Whatman GF/B) followed by three rapid rinses with 5 ml of cold buffer containing 10 xcexcM cold mepyramine. The radioactivity bound in the filters was determined by liquid scintillation spectrometry. The non-specific binding was determined by treating the animals with 30 mg/kg p.o. D-chlorpheniramine maleate. Mice treated with vehicle (methylcellulose 0.5% and tween 0.1%) were used to determine the total binding. Results are expressed as the % of specific binding at a given dose of the test compound.
The compounds of the present invention display little or no penetration of the blood brain barrier.
(4) Measurement of blood pressure and heart rate in conscious unrestrained hypertensive rats
Adult male spontaneously hypertensive rats (SHR) were operated upon in order to implant blood pressure sensors in the abdominal aorta just above the iliac bifurcation. After recovery from anaesthesia, rats were housed individually in cages placed on radio-frequency receivers. Amoxycilline (15 mg/kg, i.m., after surgery) was administered to prevent infection. The rats were allowed to recover for at least 2 weeks after transmitter implantation. Arterial blood pressure and heart rate were recorded and analysed by Dataquest V system (Data Science, St. Paul, Minn.). The animals were kept on a 12:12 hours light-dark cycle during the entire recording period. After 18 hours of fasting with water xe2x80x9cad libitumxe2x80x9d, the animals received drugs orally and then given food. Hemodynamic recordings were taken every 15 minutes, starting 4 hours before drug administration and continuing up to 24 hours after. Each recording lasted 10 seconds, and the hemodynamic values of all cycles within this period were averaged. All the animals received all the treatments, between administrations in the same rat, there was a seven day wash-out period, and a complete recovery to base-line values was ascertain. The effects of treatments on mean arterial blood pressure and heart rate were determined with one-way analysis of variance (ANOVA). A P value less than 0.05 was considered statistically significant.
The compounds of the present invention have little or no effects on blood pressure and heart rate at doses from 3 to 30 mg/kg.
From the above described results one of ordinary skill in the art can readily understand that the compounds of the present invention have excellent antihistamine and antiallergic activities. Compounds of the present invention have reduced cardiovascular and central nervous system side effects and are thus useful for the treatment of various allergic disorders, for instance, bronchial asthma, rhinitis, conjunctivitis, dermatitis and urticaria.
The present invention will be further illustrated by the following Examples. The Examples are given by way of illustration only and are not to be construed as limiting.